Chronic kidney disease (CKD) affects an estimated 19 million adults in the US, and is associated with an elevated risk of cardiovascular disease (CVD) and mortality. Clinical practice guidelines define CKD on the basis of both albuminuria and decreased kidney function, most frequently assessed by estimating the glomerular filtration rate (eGFR) using serum creatinine (SCr). National organizations have proposed including CKD in CVD risk stratification algorithms, but no large prospective studies to date have combined data on albuminuria and estimated GFR to examine CVD incidence. Recent studies in the elderly suggest Cystatin C (CysC) can provide estimates of kidney function that are more predictive of subsequent GVD events than estimates based on SCr, which are susceptible to biases due to muscle loss. CKD shares several risk factors and pathogenic mechanisms with CVD though the prospective studies of CKD have been limited. The Atherosclerosis Risk in Communities (ARIC) Study has followed 15,792 African Americans and Whites since 1987, and provided important data on CKD risk factors and consequences. We propose to collect new data and conduct systematic analyses to achieve the following aims: 1) Investigate a state of the art assessment of prevalent CKD as an independent risk factor for cardiovascular disease and mortality among 11,336 adults examined in 1996-1998. Prevalent CKD is defined by a combination of decreased kidney function (existing SCr and proposed CysC measures) and kidney damage (albuminuria). 2) Test novel predictors of declining kidney function over 6 years in a nested case-cohort design including -800 cases with estimated GFR<60 ml/min/1.73m2 based on CysC. We will focusing on markers of inflammation and advanced glycation end-products (AGEs), and 3) Identify chromosomal regions and genetic variants predictive of incident CKD. By extending ongoing genotyping we will conduct: (A) genome wide Mapping by Admixture Linkage Disequilibrium (MALD) scan in African-Americans and (B) Candidate gene study of -2,000 genes. Positive results will be tested for replication in additional identified cohorts (Jackson Heart Study, Framingham Heart Study and the Cardiovascular Heart Study). This proposal directly addresses several questions relevant to current policy issues, including how best to quantify CKD and incorporate it into CVD risk prediction algorithms. In addition, it will provide much-needed data to be shared with the larger scientific community on serologic and genetic risk factors for CKD, a growing public health concern in the US.